The receptors mediating the contractile effect of 5-hydroxytryptamine (5-HT) on the human isolated saphenous vein, obtained from 42 patients undergoing coronary bypass surgery, have been further characterized using a number of 5-HT-related drugs. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT) almost-equal-to 5-HT > methysergide almost-equal-to sumatriptan almost-equal-to alpha-methyl-5-HT almost-equal-to 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesuccinate (RU 24969) almost-equal-to 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) > 2-methyl-5-HT > 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT). Flesinoxan was inactive as an agonist. Ketanserin (1-mu-mol/l) hardly affected sumatriptan-induced contractions but it caused a rightward shift of the upper part of the concentration-response curve of 5-HT and 5-CT. The same concentration of ketanserin caused a parallel rightward shift of the concentration-response curves of alpha-methyl-5-HT and DOI with pK(B) values of 7.1 and 7.1, respectively. The responses to sumatriptan were antagonized by methiothepin (0.1-mu-mol/l), metergoline (0.1 and 1-mu-mol/l), rauwolscine (1-mu-mol/l) and cyanopindolol (1-mu-mol/l); the calculated pK(B) values were 7.3, 6.9, 7.3, 6.7 and 6.5, respectively. Contractions to 5-HT were antagonized by methysergide (1-mu-mol/l), methiothepin (0.1-mu-mol/l; pK(B) = 7.1), ICS 205-930 (1-mu-mol/l; pK(B) = 5.9) and flesinoxan (30-mu-mol/l; pK(B) = 5.3). Remarkably, the contractions elicited by 2-methyl-5-HT were not attenuated by ICS 205-930, but were antagonized by methiothepin (0.1-mu-mol/l) and, more markedly, by ketanserin (1-mu-mol/l). There was a high correlation between the functional pD2 values of 5-HT1-like receptor agonists (5-CT, 5-HT, methysergide, sumatriptan, RU 24969 and 8-OH-DPAT) and their reported binding affinities for the 5-HT1D receptor in human or calf brain membranes. Such a correlation for the antagonism of sumatriptan-induced responses was less marked than for the agonists, but of the 5-HT1-like receptor subtypes it was the highest for the 5-HT1D receptor identified in human or calf brain membranes. In 3 patients, undergoing heart transplantation, saphenous vein which had previously functioned as a graft for 6-11 years, was dissected out from the heart. Though the contractions to potassium were significantly smaller in the grafted veins, the pD2 and E(max) values (calculated as percentage of potassium-induced contractions) for 5-HT and sumatriptan were similar to those found in the veins obtained directly from the lower leg. It is concluded that contractions in the human isolated saphenous vein induced by 5-HT are mediated by 5-HT2 receptors as well as by a 5-HT1-like receptor resembling the 5-HT1D subtype found in brain membranes. It is also to be noted that 2-methyl-5-HT, considered selective for the 5-HT3 receptor, contracts the saphenous vein mainly via 5-HT2 receptors.
